A host of clinical and pre-clinical studies have demonstrated that serotonergic neurotransmission is altered both in Alcohol Use Disorders and among individuals with heightened aggression and impulsivity. Several laboratories have shown that mice bred to be lacking in the gene encoding the serotonin 5-HT1B receptor display heightened levels of aggressive behavior, increased volitional alcohol consumption, and greater self-administration of cocaine. These results clearly implicate this class of serotonin receptor in both mammalian aggression and alcohol and other drug use behavior. Consistent with this observation in the animal model, linkage has been demonstrated between polymorphisms of the gene for the human 5-HT1B receptor and antisocial forms of alcoholism. This proposed exploratory study will extend these pre-clinical and human studies by investigating both the functional responsivity of the 5-HT1B receptor, using a sumatriptan challenge paradigm, and the measured genetic variability in the locus encoding this receptor, in a study population of Alcohol Dependent men with and without Antisocial Personality Disorder. A comparison group of non-alcoholic, non-antisocial individuals, who are matched to probands on age, sex, ethnicity, and U.S. Census tract will also be studied. This latter group represents individuals who are unaffected by alcohol dependence and sociopathy, despite similar socio-environmental exposure. We believe that this approach is innovative and heuristic because it directly addresses the seential issue of the physiological ramifications of gene expression. If the serotonin 5HT1B receptor system was found to be broadly contributory to the intergenerational transmission of antisociality and substance abuse, the results would identify this system as a salient target for future genetic and psychopharmacological investigations. No less important is the possibility that psychopharmacologic agents with a high- degree of specificity for this receptor (e.g. """"""""Triptans"""""""" such as sumatriptan) could have utility as potential therapeutics for antisocial disorders associated with substance abuse.
| Moss, Howard B; Hardie, Thomas L; Dahl, John P et al. (2007) Diplotypes of the human serotonin 1B receptor promoter predict growth hormone responses to sumatriptan in abstinent alcohol-dependent men. Biol Psychiatry 61:974-8 |
| Hoffman, William F; Moore, Meredith; Templin, Raymond et al. (2006) Neuropsychological function and delay discounting in methamphetamine-dependent individuals. Psychopharmacology (Berl) 188:162-70 |
